Familial medullary carcinoma of the thyroid (MCT) is a malignant neoplasm of the calcitonin-producing C-cells of the thyroid gland, inherited in an autosomal dominant pattern with a high degree of penetrance. The tumor and its pre-malignant precursor, C-cell hyperplasia, can be detected in affected individuals by the presence of elevated serum calcitonin levels, usually following provocative challenge with an agent that stimulates calcitonin secretion. Early reports of preliminary studies have suggested that cytogenetic abnormalities may be associated with this disease. Cytogenetic abnormalities frequently in the form of chromosome instability, characterize certain other syndromes that are associated with a high incidence of cancer, e.g. preleukemia, Bloom's syndrome, Fanconi's anemia. Similarly, some families with a high incidence of cancer throughout the family j(cancer families) sometimes display chromosome instability in clinically normal members as well as affected individuals. These associations suggest that chromosome instability may be a visible manifestation of genetic susceptibility of neoplastic development. We propose to study the cytogenetics of MCT in the members of a large kindred with this disease. We plan to search for a specific chromosome abnormality, chromosome instability and/or segregational errors of chromosomes (SEC), which precede chromosome instability, that may be associated with MCT. This will require the use of a variety of cytogenetic techniques, e.g. scoring of metaphase preparations for structural and numerical aberrations, metaphase and prometaphase/prophase banding analyses and SEC analyses. Positive cytogenetic findings will be correlated with the presence of disease, as defined by histological examination or positive tests of calcitonin stimulation. The overall goal is the development of a simple, definitive cytogenetic test which will identify individuals with the MCT gene in childhood. Affected individuals could then be followed closely and treated promptly (total thyroid-ectomy at an early stage is curative). Non-affected individuals would be spared years of anxiety plus the cost and discomfort of yearly calcitonin stimulation tests. These cytogenetic findings should be applicable to other kindreds with this disease as well. In addition, basic cytogenetic data will be obtained by studying primary tumor tissue taken from surgical specimens from these patients.